DESCRIPTION: Inorganic polyphosphate is a linear polymer of hundreds of phosphate residues linked by the high-energy phosphoanhydride bonds found in ATP. In pre-biotic evolution, PolyP likely served as a precursor and catalyst in the synthesis of nucleic acids and proteins. Now poly P is found in every cell in Nature-bacteria, fungi, plants and animals. In human brain for example, the poly P chains are about 1000 residues long and concentrated in the nuclei of several cell types. In neuron-like PC-12 cells, poly P is dynamic with a turnover time of about one-hour. The purpose of this study is to gain an understanding of the biochemistry of poly P, the genetic determinants of its synthesis and utilization, and its physiological functions, especially with regard to cellular responses to nutritional deficiencies, environmental stresses and other factors in the aging process. Special emphasis will be given to the role of poly P in E. coli and other micro-organisms in which biochemical and genetic data are already in hand and the role of poly P in regulatory networks shown to be essential for survival in the stationary phase of growth. The proposed research will focus on three areas: (1) advances in methodology for high-throughput assays of poly P and related enzymes suitable for screening a thousand samples a day; (2) intensive study of the structure and function of the biosynthetic enzyme poly P kinase, and the principal exopolyphosphatases; and (3) genetic studies of networking of poly P accumulation and utilization with the regulatory proteins PhoB, Re1 A, Ntrc, and unidentified salt-stress proteins. Notable about poly P are its conservation, ubiquity, substitution for ATP, chelation, and storage of phosphate and pathogenesis of Neisseria meningitides, Helicobacter pylori, Pseudomonas aeruginosa. In view of these many possible functions, it seems likely that poly P will prove to have one or more roles in human metabolism, differentiation, and aberrations of growth and aging.